CircRNA_38959 protects liver cells from intermittent hypoxia-triggered injury and suppresses ferroptosis by interacting with IGF2BP3.

Obstructive sleep apnea (OSA) is the most prevalent sleep-related breathing disorder and is associated with cardiovascular, metabolic, neurocognitive, and mortality risk. OSA arises from recurrent upper airway collapse during sleep, producing intermittent hypoxia and sleep fragmentation. While anatomical vulnerability contributes to airway instability, a key determinant of OSA pathophysiology is the sleep-related reduction in upper airway neuromuscular activity that occurs at the wake-sleep transition. Despite this central role, no approved pharmacologic therapies have targeted the neuromuscular mechanisms underlying airway collapse. This review summarizes the biological basis of upper airway neuromuscular dysfunction in OSA, integrating insights from preclinical models of hypoglossal motor control with clinical evidence supporting neuromodulatory treatment strategies. We focus on AD109, an investigational oral therapy combining a norepinephrine reuptake inhibitor (atomoxetine) with an antimuscarinic agent (aroxybutynin), designed to counteract sleep-related withdrawal of excitatory noradrenergic drive and rapid eye movement (REM)-related muscarinic inhibition at the hypoglossal motor nucleus. Early phase clinical studies demonstrated rapid and substantial improvements in airway collapsibility and apnea-hypopnea index, providing proof of concept for this approach. Results from large phase 3 trials confirm that targeting neuromuscular dysfunction can produce reductions in airway obstruction and meaningful improvements in oxygenation, including hypoxic burden, a metric closely linked to OSA-related sequelae. Symptomatic patients also experienced improvements in fatigue, sleepiness, and snoring versus placebo. Together, these findings support neuromuscular dysfunction as a tractable therapeutic target in OSA and highlight the potential of pharmacologic strategies to address both the physiological consequences of intermittent hypoxia and patient-relevant outcomes across a broad and heterogeneous OSA population.

Chronic intermittent hypoxia-induced H2S production promotes carotid body hyperactivity via the upregulation of Sp1 S-sulfhydration and angiotensin II receptor.

Acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF), a sustained increase in phrenic motor output that arises from the balance of competing serotonin- and adenosine-driven mechanisms. Due to shifts in spinal adenosine levels, pLTF exhibits a diurnal cycle, where 15, 1-min hypoxic episodes elicit robust serotonin-dependent pLTF during the diurnal rest phase (∼130%) but are markedly attenuated in mid-active phase rats (∼30%) due to undermining effects from elevated spinal adenosine. Mechanistic studies of pLTF typically use anesthetized, paralyzed, mechanically ventilated rats with bilateral cervical vagotomy to prevent ventilator entrainment. However, vagotomy increases arterial pressure, which may protect spinal cord perfusion during hypoxic episodes. Here, we tested the hypothesis that intact vagus nerves diminish spinal oxygenation and pLTF expression. Rats with intact vagus nerves had lower arterial pressure and spinal cord oxygen tensions during hypoxic episodes, despite equivalent hypoxemia. As spinal cord hypoxia promotes adenosine accumulation, expected to constrain serotonin-driven pLTF, we hypothesized that intact vagal feedback blunts rest-phase pLTF and abolishes diurnal variations in response to AIH (15, 1-min episodes). With intact vagi, increased phrenic burst amplitude 90 min post-AIH was markedly attenuated in the mid-rest (43 ± 63% baseline), but not mid-active phase (43 ± 25%), suppressing the magnitude of diurnal variation. Cervical spinal delivery of the A2a receptor antagonist MSX-3 restored robust pLTF in both diurnal phases; selective A2a receptor knockdown within phrenic motor neurons enhanced pLTF during mid-rest but not mid-active phase. Thus, intact vagus nerves indirectly shift the spinal serotonin/adenosine balance during hypoxia, suppressing diurnal variations in pLTF magnitude.NEW & NOTEWORTHY Acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF) via competing serotonin versus adenosine-driven signaling cascades. pLTF mechanisms are typically studied in anesthetized, vagotomized rats. We report in anesthetized rats that intact vagus nerves: 1) lower blood pressure and spinal oxygen tension during hypoxic episodes; 2) increase the adenosine constraint of serotonin-driven pLTF; and 3) abolish diurnal variations in pLTF magnitude. Thus, vagal feedback regulates pLTF via indirect effects on the spinal serotonin/adenosine balance.

Effect of chronic intermittent hypoxia on apoptosis based on microbiome-based co-metabolomics.

Obstructive sleep apnea (OSA) is frequently complicated by hypertension, with approximately 60% of patients exhibiting both conditions. However, the epigenetic mechanisms underlying this comorbidity remain largely unexplored. N6-methyladenosine (m6A), the most abundant internal RNA modification, has emerged as a critical regulator of cardiovascular pathology, yet its role in OSA-associated hypertension (OSA-HTN) is unknown. Here, we investigated the contribution of m6A RNA methylation to OSA-HTN pathogenesis. In a chronic intermittent hypoxia (CIH) mouse model and hypoxia-stimulated aortic vascular smooth muscle cells (AVSMCs), we observed marked inflammatory injury, pyroptosis, and decreased expression of methyltransferase-like 3 (METTL3) along with global m6A levels. Overexpression of METTL3 significantly attenuated hypoxia-induced pyroptosis and inflammation by downregulating SRY-box transcription factor 4 (SOX4), a pro-inflammatory transcription factor. Mechanistically, CIH suppressed YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2), an m6A reader that directly binds SOX4 mRNA, while METTL3-mediated m6A modification enhanced YTHDF2-dependent SOX4 mRNA degradation. Knockdown of YTHDF2 abolished the suppressive effect of METTL3 on SOX4 stability, confirming a METTL3-m6A-YTHDF2 regulatory axis. This METTL3-dependent regulation of YTHDF2-SOX4 interaction and SOX4 mRNA decay was also validated in mouse aortic endothelial cells. Furthermore, in vivo silencing of SOX4 alleviated CIH-induced pyroptosis and inflammation in cardiac and aortic tissues. Notably, pharmacological activation of METTL3 or METTL3 overexpression similarly attenuated CIH-induced cardiac and aortic tissue injury in OSA-HTN mice. In conclusion, our findings identify a novel METTL3-YTHDF2-SOX4 axis that governs hypoxia-induced pyroptosis and inflammation, providing new mechanistic insights into the epigenetic regulation of OSA-HTN and highlighting potential therapeutic targets.

Physiological predictors of respiratory motor plasticity: A machine-learning reappraisal of phrenic motor facilitation.

ICAM-1 targeted extracellular vesicles loaded with HC-070 mitigate vascular oxidative stress and inflammation in obstructive sleep apnea hypopnea syndrome by inhibiting TRPC5.

Obstructive sleep apnea (OSA) is highly prevalent and triples cardiovascular risk. Intermittent hypoxia during apneas impairs endothelial cell (EC) protection against complement, which initiates endothelial inflammation and increases cardiovascular risk. This process appears to be linked to altered cellular cholesterol metabolism. However, whether and how intermittent hypoxia alters endothelial cholesterol homeostasis and whether those changes affect endothelial inflammation in patients with OSA are unclear. ECs were harvested from the forearm vein from patients with OSA (n=24; age, 44±14 years; 38% female; body mass index, 36±10 kg/m2) and OSA-free controls (n=19; age, 39±14 years; 74% female; body mass index, 29±9 kg/m2). Cultured human umbilical vein ECs exposed to intermittent hypoxia (alternating 30-minute 21% O2 for normoxia/30-minute 2% O2 for hypoxia for 8 hours), 2% O2 for 8 hours (continuous hypoxia), or normoxia were used as the in vitro model. Intermittent hypoxia-induced endoplasmic reticulum stress increases interaction of endoplasmic reticulum-bound VAP-B (vesicle-associated membrane protein-associated protein B) with Derlin-1 (degradation in endoplasmic reticulum protein 1), which, in turn, impairs VAP-B interaction with endolysosomal compartment-bound ORP1L (oxysterol-binding protein-related protein 1 long form), leading to retention of cholesterol in the endolysosomal compartment in ECs in OSA. The consequent increase in cholesterol content in the EC plasma membrane promotes internalization of the complement inhibitor CD59, thereby increasing deposition of the terminal complement membrane attack complex on ECs and initiating inflammation. Low levels of positive airway pressure therapy reversed OSA-induced alteration in interactions of VAP-B with both Derlin-1 and ORP1L in patients with OSA. Using a direct approach to study endothelium, we have identified altered endothelial intracellular cholesterol trafficking and metabolism as mechanisms underlying reduced protection against complement activity and increased endothelial inflammation, which, over time, increases cardiovascular risk in OSA.

Obstructive sleep apnea (OSA) is a highly prevalent multisystem disorder characterized by intermittent hypoxia, autonomic dysregulation, and sleep fragmentation. Storage-predominant lower urinary tract symptoms (LUTS)-including urgency, urgency incontinence, and overactive bladder-also involve central and autonomic neural pathways. Although OSA has been independently linked to nocturia and cognitive impairment, no large-scale studies have examined OSA, storage LUTS, and neurocognitive outcomes concurrently in a population with male LUTS. Using the TriNetX Research Network, we conducted a retrospective cohort study of men ≥ 50 years with the diagnosis code "BPH without baseline LUTS". Two cohorts were constructed, consisting of men who received a diagnosis of obstructive sleep apnea within 1 year after the initial BPH diagnosis and those with no documented diagnosis of OSA at any time. Propensity score matching (1:1) produced two balanced cohorts of 89,074 patients each. Ten outcomes representing LUTS and cognitive conditions were evaluated using risk ratios, hazard ratios, and Kaplan-Meier analyses. OSA was associated with increased risk and earlier onset of urgency and urgency incontinence, overactive bladder, frequency of micturition, and neuromuscular bladder dysfunction. OSA was strongly associated with mild cognitive impairment and physiologic neuropsychiatric disorders, with no difference in Alzheimer's disease incidence. These findings raise the possibility that lower urinary tract symptoms deserve greater attention in the evaluation of men with OSA, specifically in relation to nervous system as opposed to purely cardio-renal mechanisms.

Sleep is an active period of profound autonomic fluctuation, cycling between the parasympathetic dominance of nonrapid eye movement sleep and the sympathetic/parasympathetic volatility of rapid eye movement sleep. Sleep-disordered breathing, a spectrum of disorders marked by recurrent ventilatory instability and intermittent hypoxia during sleep, particularly obstructive sleep apnea, pathologically amplifies this volatility, transforming sleep into a nightly cascade of severe autonomic and hemodynamic stress. The cardinal features of sleep-disordered breathing, intermittent hypoxia, recurrent arousals, and marked intrathoracic pressure swings, act synergistically to drive chronic, 24-hour sympathetic overactivity, chemoreflex sensitization, and maladaptive neuroplasticity. These effects are mediated at a cellular level by oxidative stress, systemic inflammation, endothelial dysfunction, and neuroendocrine dysregulation. This persistent autonomic reset provides a direct mechanistic link to cardiovascular consequences. It is likely a primary driver of hypertension, blunting the nocturnal blood pressure dip and promoting sustained 24-hour sympathoexcitation. It fosters a proarrhythmic substrate for atrial fibrillation through mechanical stress, which drives atrial remodeling and autonomic conflict. Furthermore, sleep-disordered breathing contributes to myocardial ischemia by increasing myocardial oxygen demand and promoting a prothrombotic state. Beyond chronic disease, sleep-related autonomic shifts can act as acute triggers for malignant arrhythmias in individuals with vulnerable substrates, such as inherited channelopathies, a risk that may be significantly amplified by comorbid sleep-disordered breathing. This review delineates the critical neural and cellular pathways connecting sleep, autonomic dysregulation, and cardiovascular risk.

Relationship between changes in intestinal desulfovibrio levels and oxygen desaturation in patients with obstructive sleep apnea syndrome.

Epigenetic mechanisms are considered adaptive regulators of gene expression, yet mechanisms driving aging-associated DNA methylation remain unclear. Prior work hinted that epigenetic aging might reflect a response to oxygen availability, with age‑differential methylation in immune cells enriched near binding sites for hypoxia‑responsive factors ARNT and REST. To test this hypothesis, we exposed adult (11 months) and old (23 months) mice to 1 month of intermittent hypoxia (IH) followed by normoxic recovery. IH induced epigenetic age acceleration in lungs, spleen, and heart in old mice only. This acceleration reversed upon return to normoxia. Reversible shifts were enriched at bivalent domains and PRC2 targets, indicating oxygen-sensitive chromatin remodeling. Human translational validation in young adults at high altitude (5260 m) confirmed rapid, conserved epigenetic aging. Our findings establish oxygen availability as a primary, conserved modulator of epigenetic aging across tissues and species, showing that oxygen fluctuations are a potent, reversible driver of epigenetic aging.

Although their functions have long been disputed, pulmonary neuroepithelial bodies (NEBs) are now considered complex, multifunctional units implicated in vagal sensory signaling within the brain–lung axis. A widely proposed function of NEBs is that their neuroendocrine cells would be able to sense acute airway hypoxia, triggering Ca² ⁺ -dependent transmitter release and the subsequent activation of vagal afferents that transfer the hypoxic information to the central nervous system (CNS). However, physiological evidence for the latter well-documented hypothesis is so far inconclusive. Using a confocal live-cell imaging model, based on murine precision-cut lung slices (PCLSs), this study was designed to directly visualize hypoxia-induced activation of NEB cells, including associated Ca² ⁺ -mediated exocytotic events that would support CNS-directed signaling. In PCLSs from prenatal and postnatal C57BL/6 mice, including GAD67-GFP mice, we monitored changes in intracellular Ca²⁺ ([Ca²⁺]i), mitochondrial membrane potential, and reactive oxygen species (ROS) during acute and intermittent hypoxia, as well as after ROS scavenging. Whole-mount mouse carotid bodies served as positive controls. Carotid body glomus cells showed robust hypoxia-induced [Ca²⁺]i rises, confirming assay sensitivity. In contrast, neither acute (2 or 12% O₂) nor intermittent hypoxia elicited [Ca²⁺]i increases in NEBs or delayed activation of adjacent Clara-like cells at any developmental stage. NEBs remained responsive to K+-induced depolarization, though excitability appeared to decrease during hypoxia. Hypoxia caused rapid, reversible mitochondrial depolarization in NEBs and ciliated epithelial cells, accompanied by a modest ROS increase in all airway epithelial cells. Tempol did not uncover any [Ca²⁺]i responses. Whereas control airway epithelium and carotid body expressed all NADPH oxidase subunits, the NEB microenvironment appeared to lack clear expression of several components. We conclude that mouse NEBs do not exhibit Ca² ⁺ -mediated exocytotic responses to hypoxia and that NADPH oxidase is unlikely to function as their O₂ sensor. These findings challenge a direct NEB-to-brain signaling pathway for acute hypoxia, but support local, paracrine functions related to airway oxygenation.

Lung cancer remains a major challenge in clinical treatment, as current therapeutic strategies often fail to effectively halt disease progression. Chronic intermittent hypoxia (CIH), a hallmark pathological feature of obstructive sleep apnea (OSA), has been implicated in promoting tumor invasion and metastasis. This study aimed to investigate the potential of hydrogen as an innovative adjunctive therapy for lung cancer. To evaluate the therapeutic effects of hydrogen, both in vitro and in vivo models were established. In vitro, an intermittent hypoxia (IH) tumor cell-macrophage co-culture system was used to assess cell proliferation, migration, and macrophage polarization. In vivo, tumor growth was monitored in a CIH mouse model, and tissue samples were subsequently analyzed via immunohistochemistry and western blot. Our results demonstrated that hydrogen exerted significant antitumor effects in vivo. Mechanistically, this effect was associated with a shift in macrophage polarization toward the pro-inflammatory M1 phenotype and suppression of the CCL2-CCR2 signaling axis. In addition, in vitro studies revealed that hydrogen directly inhibited lung cancer cell survival and migration, and downregulated key components of the CCL2-CCR2 pathway, mirroring the effects observed with a CCR2 inhibitor. These findings highlighted that hydrogen treatment suppressed tumor growth by modulating the tumor immune microenvironment and inhibiting angiogenesis. Collectively, our results suggested that hydrogen may represented a novel and promising therapeutic strategy for lung cancer.

Oxygen extremes, inflammation, and neonatal breathing.

ADORA2B/ador-1 is required for multi-system transcriptional adaptation to mild hypoxia and healthspan extension in C. elegans.

BackgroundThe aim of this study was to assess selected retinal parameters and choroidal thickness in patients with obstructive sleep apnea.Material/MethodsForty-nine patients (98 eyes) were included in this prospective cross-sectional study: 33 patients with moderate or severe OSA (66 eyes) and 16 controls with no or mild OSA (32 eyes). Control and study group participants were classified according to polysomnography results. Foveal avascular zone parameters, vessel density of the superficial (SVD) and deep (DVD) capillary plexuses in the macular region, and choroidal thickness were assessed using the AngioVue Imaging System (Optovue). Results were compared between the study and control groups. Correlations between age and these measurements were calculated.ResultsThere were no significant differences in SVD or DVD between the groups (all P>0.05). Foveal avascular zone area and perimeter were significantly larger in the OSA group than in controls (P=0.0163 and P=0.0236, respectively). No significant differences were observed in foveal vessel density within 300 μm (FD-300) values (P=0.2852). Choroidal thickness measurements were significantly higher in the OSA group overall (P=0.0054), although these values showed a moderate negative correlation with age (r=−0.36, P=0.0002).ConclusionsSubtle retinal microvascular alterations and increased choroidal thickness in OSA may indicate an impact of intermittent hypoxia on ocular structures. The relatively small study sample represents a limitation of the study.

BackgroundBrachycephalic obstructive airway syndrome (BOAS) affects the upper airways of brachycephalic dogs and might alter heart rate variability (HRV).Hypothesis/ObjectivesThis study aimed to evaluate HRV in dogs with BOAS during wakefulness and sleep.AnimalsForty-six client-owned dogs: 34 brachycephalic (with and without BOAS) and 12 non-brachycephalic controls.MethodsA prospective cross-sectional study utilizing 24-h Holter monitoring and segments recorded during wakefulness and sleep. The evaluated variables included heart rate, mean RR interval, the longest sinus pause, and HRV indices calculated over 24 h, as well as during segments of wakefulness and sleep: corrected standard deviation of NN intervals (cSDNN), corrected root mean square of successive differences (cRMSSD), the vagal tone index (VVTI), and Poincaré plot analysis.ResultsIn the 24-h Holter analysis, BOAS dogs showed significantly higher values than controls, particularly in cSDNN (0.365 [IQR: 0.306-0.465] vs 0.246 [IQR: 0.208-0.359] ms, P = .0058) and cRMSSD (0.476 [IQR: 0.409-0.599] vs 0.312 [IQR: 0.259-0.462] ms, P = .0119). Sleep was associated with higher cSDNN, cRMSSD, and VVTI in all groups (StateSleep estimates: 0.105 [95% CI, 0.062-0.149], 0.426 [95% CI, 0.264-0.588], and 1.758 [95% CI, 1.378-2.139], respectively; all P < .001), with no significant group-by-state interaction for these variables. Presence of BOAS was moderately correlated with the longest sinus pause (r = 0.4197, P = .0023), cSDNN (r = 0.4600, P = .0006), and cRMSSD (r = 0.4214, P = .0018).Conclusions and clinical importanceThe presence of BOAS influences autonomic modulation more than the dogs’ craniofacial conformation. Differences in HRV were more pronounced in awake dogs, likely due to chronic respiratory alterations and intermittent hypoxia.

Recent advances in prenatal and neonatal care have significantly improved the survival rates of extremely low gestational age new-borns (ELGANs), born at ≤28weeks of gestation. Exposure to low oxygen levels in the intrauterine environment during the last trimester is crucial for normal organ development. The extrauterine environment is highly toxic to ELGANs. Exposure to ambient and supplemental oxygen, intermittent hypoxia, excessive glucocorticoids, hyperalimentation, infections and mechanical ventilation, elevated ROS levels, coupled with insufficient antioxidant defences, lead to oxidative stress. Oxidative stress leads to damages in cell membranes, mitochondria and DNA, negatively impacting developing cells and tissues in all organs. ELGANs are at increased risk of developing acute prematurity-related diseases such as bronchopulmonary dysplasia, pulmonary hypertension and acute kidney injury. As ELGANs age, they face a higher risk of chronic diseases such as chronic obstructive pulmonary disease, cardiovascular disease, chronic kidney disease, type 2 diabetes. and other metabolic diseases later in life. Collectively, these chronic diseases are associated with accelerated ageing and increased mortality in former ELGANs. This review presents the epidemiology of clinical disorders affecting the respiratory, cardiovascular, renal and metabolic systems across the lifespan in ELGANs. It explores the roles of early oxidative stress during the last trimester of organ development in activating signalling pathways that promote cellular senescence and epigenetic reprogramming, leading to acute and chronic disease.